The objective of the current Epicenter initiative is to establish a network of academic investigators to translate basic, epidemiologic and technologic discoveries into new strategies to prevent hospital-acquired infections (HAI) and antimicrobial resistance (AR). The WU /BJC Epicenter is internationally recognized for research productivity and leadership preventing HAI and AR. WU has outstanding research infrastructure and perennially ranks in the top 5 medical centers in the U.S. BJC is a 13 hospital integrated healthcare delivery system with long term care facilities, outpatient clinics, and physician practices connected with shared electronic medical records, clinical data repositories and billing systems. BJC includes two "top 10" hospitals, Barnes-Jewish Hospital and St. Louis Children's Hospital, which are both NHSN hospitals and 11 acute care hospitals including large and small, suburban and rural hospitals which are joining NHSN. The BJC Infection Prevention and Epidemiology Consortium uses standardized surveillance, data analysis, policies and procedures in all 13 hospitals. We have the necessary infrastructure to participate in the next Epicenter Program. We organized a team of basic, translational and clinical investigators with expertise in infectious disease, healthcare epidemiology, microbiology, critical care and basic science to work together to perform TO, T1 and T2 studies to discover and test new methods to prevent HAI and AR. We set broad goals focused on developing and evaluating novel strategies to reduce central line-associated blood stream infections (CLABSI), ventilator-associated pneumonia (VAP), Clostridium difficile infections (CDI) and catheter-associated urinary tract infections (CAUTI). To achieve these goals, we propose the following Specific Aims: 1. Develop, Implement and Evaluate a Central Line Care "Maintenance Bundle" to Reduce Central Line- Associated Blood Stream Infections (CLABSI) Outside ICU Settings. 2. Determine if Use of the Probiotic, Lactobacillus Rhamnosus GG Can Reduce Ventilator-Associated tracheobronchitis (VAT), Ventilator-Associated Pneumonia (VAP) and Colonization with Antimicrobial Resistant (AR) Bacteria in High Risk Patients. 3. Determine if Use of Primary Prophylaxis with Once Daily, Low Dose Oral Fidaxomicin Can Decrease C. difficile Acquisition and C. difficile Infection (CDI) Incidence in High Risk Patients. 4. Conduct First-in-Human Studies to Document the Natural History of Bacterial Biofilm Biomarkers in Patients with Urinary Catheters and Compare Biomarker Profiles in Catheterized Patients with Negative Urine Cultures, Asymptomatic Bacteriuria and Symptomatic Urinary Tract Infections. New knowledge, products and tools will result from the research proposed in these aims. This knowledge will be able to be translated into practice and used to prevent HAI in diverse healthcare settings across the U.S. Preventing HAI and AR will reduce morbidity and mortality and reduce costs for hospitalized patients.